PROJECT SUMMARY: Studies in Natural Product Synthesis Natural products continue to play an important role in drug discovery and development. As such, natural product synthesis efforts can have a profound impact on the development of therapeutically relevant compositions of matter. This is due not only to successes that deliver rare natural products for which an abundant natural source has yet to be identified, but also due to fact that the synthetic pathways elucidated provide a means to access novel natural product analogs that can drive medicinal chemistry pursuits. The current program aims to establish a focused effort in natural product synthesis, where developments in organic chemistry will derive from our attempt to identify new synthesis strategies and reaction methods that have been inspired by dauntingly complex targets that are known to possess an array of biological activities. Specifically, we are initiating this program with natural product targets that have intricately functionalized polycyclic skeletons that demand creative advances in organic chemistry to accomplish efficient synthesis. Targets for the initial phase of this program are ryanodol and vinigrol, both of which continue to represent substantial challenges to modern organic chemistry. Our efforts targeting ryanoids focus on a new synthesis strategy for the assembly of highly oxygenated carbocycles. This strategy has already led to a novel annulation method that offers retrosynthetic strategies that are complementary to the Diels?Alder reaction as well as the Robinson and Pauson?Khand annulation reactions. Our vinigrol-inspired efforts are driven by the desire to establish its polycyclic skeleton through a novel sigmatropic rearrangement cascade and the use of a late- stage transannular cyclization to establish the cis-decalin core in concert with the ansa-bridge. Overall, development of this program promises the delivery of science that will have a significant impact on organic chemistry through offering novel synthesis strategies and reaction methods capable of delivering natural product-inspired and highly complex compositions of matter in a concise manner. 1